Published Online
on March 28, 2005

A more recent version of this article appeared on April 5, 2005

This Article Full Text (PDF) All Versions of this Article: 111/13/1619    most recent 01.CIR.0000160363.30639.37v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hwang, C.-W. Articles by Edelman, E. R. Search for Related Content PubMed PubMed Citation Articles by Hwang, C.-W. Articles by Edelman, E. R. Related Collections Cardiovascular Pharmacology Restenosis Animal models of human disease Arterial thrombosis Coagulation Catheter-based coronary interventions: stents

Submitted on June 15, 2004
Revised on December 13, 2004
Accepted on December 17, 2004

Thrombosis Modulates Arterial Drug Distribution for Drug-Eluting Stents

Chao-Wei Hwang MD, PhD^*, Andrew D. Levin MS, Michael Jonas MD, Pamela H. Li BS, and Elazer R. Edelman MD, PhD

From Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge (C.H., A.D.L., M.J., P.H.L., E.R.E.); and Department of Medicine (C.H.) and Cardiovascular Division, Department of Medicine (M.J., E.R.E.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.

^* To whom correspondence should be addressed. E-mail: cwhwang{at}post.harvard.edu.

Background--Drug-eluting stents deliver potent compounds directly to arterial segments but can become clot laden when deployed. The question arises as to whether thrombi affect drug elution and arterial uptake.

Methods and Results--Paclitaxel transport and retention were assessed in clots of different blood components. Diffusivity, affected by clot organization, is fastest in fibrin (347 µm²/s), slower in fibrin-red blood cell clots (34.98 µm²/s), and slowest in whole-blood clots (3.55 µm²/s). Blood cells bind and retain paclitaxel such that levels in clot increase linearly with red cell fraction. At physiological hematocrit, clot retains 3 times the amount of paclitaxel in surrounding solutions. Computational models predict that the potential of thrombus to absorb, retain, and release drug or to act as a barrier to drug delivery depends on clot geometry and strut position in clot relative to the vessel wall. Clot between artery and stent can reduce uptake 10-fold, whereas clot overlying the stent can shield drug from washout, increasing uptake. Model assumptions were confirmed and predictions were validated in a novel rat model that introduces thrombosis within stented aortas where nonocclusive thrombus acts as capacitive space for drug and shifts drug levels to decrease tissue uptake 2-fold.

Conclusions--Thrombus apposed on stents creates large variations in drug uptake and can act to either increase or decrease wall deposition according to the clot and stent geometry. Arterial deposition of drug from stents deployed in clots will be highly variable and unpredictable unless the clot can be adequately controlled or removed.

Key words: stents • thrombus • thrombosis • drugs • restenosis

This article has been cited by other articles:

				A. V. Finn, G. Nakazawa, F. Kolodgie, and R. Virmani Drug eluting or bare metal stent for acute myocardial infarction: an issue of safety? Eur. Heart J., August 1, 2009; 30(15): 1828 - 1830. [Full Text] [PDF]

				N. Gonzalo, P. Barlis, P. W. Serruys, H. M. Garcia-Garcia, Y. Onuma, J. Ligthart, and E. Regar Incomplete Stent Apposition and Delayed Tissue Coverage Are More Frequent in Drug-Eluting Stents Implanted During Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction Than in Drug-Eluting Stents Implanted for Stable/Unstable Angina: Insights From Optical Coherence Tomography J. Am. Coll. Cardiol. Intv., May 1, 2009; 2(5): 445 - 452. [Abstract] [Full Text] [PDF]

				G. Guagliumi and M. Costa From a Foggy Sight to a Clear Vision J. Am. Coll. Cardiol. Intv., May 1, 2009; 2(5): 467 - 469. [Full Text] [PDF]

				G. Nakazawa, A. V. Finn, M. Joner, E. Ladich, R. Kutys, E. K. Mont, H. K. Gold, A. P. Burke, F. D. Kolodgie, and R. Virmani Delayed Arterial Healing and Increased Late Stent Thrombosis at Culprit Sites After Drug-Eluting Stent Placement for Acute Myocardial Infarction Patients: An Autopsy Study Circulation, September 9, 2008; 118(11): 1138 - 1145. [Abstract] [Full Text] [PDF]

				A. V. Finn, G. Nakazawa, E. Ladich, F. D. Kolodgie, and R. Virmani Does underlying plaque morphology play a role in vessel healing after drug-eluting stent implantation? J. Am. Coll. Cardiol. Img., July 1, 2008; 1(4): 485 - 488. [Full Text] [PDF]

				C. S. Rihal Drug-Eluting Stents for ST-Segment Elevation Myocardial Infarction: Treatment of Choice or Is Discretion the Better Part of Valor? J. Am. Coll. Cardiol. Intv., June 1, 2008; 1(3): 233 - 235. [Full Text] [PDF]

				G. Sianos, M. I. Papafaklis, J. Daemen, S. Vaina, C. A. van Mieghem, R. T. van Domburg, L. K. Michalis, and P. W. Serruys Angiographic Stent Thrombosis After Routine Use of Drug-Eluting Stents in ST-Segment Elevation Myocardial Infarction: The Importance of Thrombus Burden J. Am. Coll. Cardiol., August 14, 2007; 50(7): 573 - 583. [Abstract] [Full Text] [PDF]

				M. Valgimigli, G. Campo, C. Arcozzi, P. Malagutti, R. Carletti, F. Ferrari, D. Barbieri, G. Parrinello, G. Percoco, and R. Ferrari Two-Year Clinical Follow-Up After Sirolimus-Eluting Versus Bare-Metal Stent Implantation Assisted by Systematic Glycoprotein IIb/IIIa Inhibitor Infusion in Patients With Myocardial Infarction: Results From the STRATEGY Study J. Am. Coll. Cardiol., July 10, 2007; 50(2): 138 - 145. [Abstract] [Full Text] [PDF]

				D. R. Holmes Jr, D. J. Kereiakes, W. K. Laskey, A. Colombo, S. G. Ellis, T. D. Henry, J. J. Popma, P. W.J.C. Serruys, T. Kimura, D. O. Williams, et al. Thrombosis and Drug-Eluting Stents: An Objective Appraisal J. Am. Coll. Cardiol., July 10, 2007; 50(2): 109 - 118. [Abstract] [Full Text] [PDF]

				A. V. Finn, G. Nakazawa, M. Joner, F. D. Kolodgie, E. K. Mont, H. K. Gold, and R. Virmani Vascular Responses to Drug Eluting Stents: Importance of Delayed Healing Arterioscler Thromb Vasc Biol, July 1, 2007; 27(7): 1500 - 1510. [Abstract] [Full Text] [PDF]

				M. Joner, A. V. Finn, A. Farb, E. K. Mont, F. D. Kolodgie, E. Ladich, R. Kutys, K. Skorija, H. K. Gold, and R. Virmani Pathology of Drug-Eluting Stents in Humans: Delayed Healing and Late Thrombotic Risk J. Am. Coll. Cardiol., July 4, 2006; 48(1): 193 - 202. [Abstract] [Full Text] [PDF]

				S. R. Dixon, C. L. Grines, and W. W. O'Neill The Year in Interventional Cardiology J. Am. Coll. Cardiol., April 18, 2006; 47(8): 1689 - 1706. [Full Text] [PDF]

				R. Wessely, A. Schomig, and A. Kastrati Sirolimus and Paclitaxel on Polymer-Based Drug-Eluting Stents: Similar But Different J. Am. Coll. Cardiol., February 21, 2006; 47(4): 708 - 714. [Abstract] [Full Text] [PDF]